Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
  • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
  • C07D451/06—Oxygen atoms
  • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics

Definitions

• the present invention relates to new difurylglycolic acid esters of the general formula 1
• the present invention relates to compounds of the general formula 1_
• A is a divalent radical selected from the group consisting of
• X is a single negatively charged anion, preferably an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate ;
• R is hydrogen, hydroxy, methyl, ethyl, -CF3, CHF 2 or fluorine;
• R1 and R 2 are the same or different, -Cj-Cs-alkyl, which may optionally be substituted by -C3-Cß-cycloalkyl, hydroxy or halogen, or R 1 and R 2 together form a -C3-C5-alkylene bridge;
• R 3 and R 3 ' the same or different, furyl, which may optionally be mono-, di- or trisubstituted by a radical selected from the group consisting of -C- ⁇ -C-4-alkyl, -CiC ⁇ alkyloxy, hydroxy , -CF3, -CHF2, CN, NO2 or halogen.
• A is a double-bonded residue selected from the group consisting of
• Chloride bromide, 4-toluenesulfonate and methanesulfonate, preferably bromide;
• R is hydroxy, methyl or fluorine;
• R 1 and R 2 are the same or different, methyl, ethyl or fluoroethyl;
• R 3 and R 3 ' the same or different, mean furyl, which may optionally be mono- or disubstituted by a radical selected from the group consisting of methyl, methyloxy, hydroxy, -CF3, -CHF2, fluorine or chlorine.
• R is hydroxy, methyl or fluorine, preferably hydroxy;
• R 1 and R 2 are the same or different, methyl or ethyl, preferably methyl;
• R 3 and R 3 ' the same or different, mean furyl, which may optionally be mono- or disubstituted by a radical selected from the group consisting of -CF3, -CHF2 or fluorine.
• A is a double-bonded residue selected from the group consisting of
• R is hydroxy or methyl, preferably hydroxy
• R " ! And R 2 are the same or different, methyl or ethyl, preferably methyl;
• R 3 and R 3 ' mean furyl, which may optionally be mono- or disubstituted by fluorine.
• the invention relates to the respective compounds of formula 1, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates.
• di- (2-furyl) glycolic acid tropenol ester methobromide Di- (2-furyl) -glykolklarescopinester methobromide;
• furyl is the group
• the furyl group according to the radicals R 3 and R 3 ' can be unsubstituted or carry substituents in accordance with the definitions given above.
• the two furyl groups of the radicals R 3 and R 3 ' may have identical or different substituents.
• those compounds are preferred according to the invention in which, provided that the furyl groups in R 3 and R 3 'have substituents, both groups have the same substituents.
• Compounds in which at least one of the radicals R 3 and R 3 'represents an unsubstituted furyl group are particularly preferred. Both R 3 and R 3 'are particularly preferably unsubstituted furyl.
• the alkyl groups are branched and unbranched alkyl groups with 1 to 5 carbon atoms. Examples include: methyl, ethyl, propyl or butyl.
• the abbreviations Me, Et, Prop or Bu may also be used to denote the groups methyl, ethyl, propyl or butyl.
• the definitions propyl and butyl encompass all conceivable isomeric forms of the respective radicals.
• propyl includes n-propyl and iso-propyl
• butyl includes iso-butyl, sec. Butyl and tert-butyl, etc.
• alkylene groups are branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms. Examples include: methylene, ethylene, propylene or butylene.
• alkyloxy groups are branched and unbranched alkyl groups having 1 to 4 carbon atoms which are linked via an oxygen atom. Examples include: methyloxy, ethyloxy, propyloxy or butyloxy.
• the abbreviations MeO-, EtO-, PropO- or BuO- are also used to denote the groups methyloxy, ethyloxy, propyloxy or butyloxy.
• the definitions propyloxy and butyloxy encompass all conceivable isomeric forms of the respective radicals.
• propyloxy includes n-propyloxy and iso-propyloxy
• butyloxy includes iso-butyloxy, sec. Butyloxy and tert-butyloxy, etc.
• the term alkyloxy is also used in the context of the present invention
• alkoxy Name used alkoxy. Accordingly, the terms methoxy, ethoxy, propoxy or butoxy are also used to designate the groups methyloxy, ethyloxy, propyloxy or butyloxy.
• Halogen in the context of the present invention is fluorine, chlorine, bromine or iodine. Unless stated otherwise, fluorine and bromine are preferred halogens.
• the group CO denotes a carbonyl group.
• the compounds according to the invention can be prepared in part analogously to procedures already known in the prior art (Scheme 1).
• the carboxylic acid derivatives of the formula 3 are known in the prior art or can be obtained by synthetic methods known in the prior art. If only appropriately substituted carboxylic acids are known in the prior art, the compounds of the formula 3 can also be obtained directly from these by acid- or base-catalyzed esterification with the corresponding alcohols or by halogenation with the corresponding halogenation reagents.
• the esters of the general formula 4 can be accessed by reaction with the carboxylic acid derivatives of the formula 3 in which R 'is, for example, chlorine or a C 1 -C 4 -alkyloxy radical.
• R 'is C 1 -C 4 -alkyloxy this reaction can, for example, in a sodium melt at elevated temperature, preferably at about 50-150 ° C, particularly preferably at about 90-100 ° C at low pressure, preferred at below 500mbar, particularly preferably at below 75mbar.
• the compounds of formula 4 thus obtained can be converted into the target compounds of formula 1 by reaction with the compounds R 2 -X, in which R 2 and X can have the meanings mentioned above.
• This synthesis step can also be carried out in analogy to the synthesis examples disclosed in WO 92/16528.
• R 1 and R 2 together form an alkylene bridge the addition of the reagent R 2 -X is not necessary, as can be seen by the person skilled in the art.
• the compounds of formula 4 have a suitably substituted radical R 1 (for example -C3-C-5-alkylene-halogen) according to the definitions given above and the compounds of formula 1 are prepared by intramolecular quaternization of the amine.
• the derivatives 4 in which the nitrogen bicyclus is a scopin derivative can be obtained by oxidation (epoxidation) of compounds of the formula 4 in which the nitrogen bicyclus is a tropenyl Rest is.
• oxidation epoxidation
• this can be done as follows.
• Dimethylformamide suspended and then heated to a temperature of about 30-90 ° C, preferably 40-70 ° C.
• a suitable oxidizing agent is then added and the mixture is stirred at a constant temperature for 2 to 8 hours, preferably 3 to 6 hours.
• the preferred oxidizing agent is vanadium pentoxide mixed with H2O2, particularly preferably H2O2
• radicals A, R, R 1 , R 3 and R 3 ' may have the meanings given above, optionally in the form of their acid addition salts.
• salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate toluate and hydrochloride pentahydrate and hydrobenzoate toluate and hydrochloride pentahydrate and hydrobenzoate toluene and hydrobenzonate and hydrobenzonate and hydrobenzonate and hydrobenzoate toluene and hydrobenzonate and hydrobenzoate toluate and hydrobenzonate and hydrobenzonate and hydrobenzoate toluate and hydrobenzonate and hydrobenzonate and hydrobenzoate toluate and hydrobenzonate and hydrobenzonate and hydrobenzoate toluate and hydrochloride preferably. Hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate understood
• Another aspect of the present invention relates to the use of compounds of general formula 2 for the preparation of the compounds of general formula 4. Furthermore, the present invention relates to the use of Compounds of the general formula 2 as starting material for the preparation of the compounds of the general formula 1 .. The present invention further relates to the use of the compounds of the general formula 4 as an intermediate in the preparation of the compounds of the general formula 1 ..
• Example 1 Di- (2-furyl) glycolic acid tropenol ester methobromide
• Di- (2-furyl) -qlvkolklarescopinester-Methobromid 0.95 g (0.003 mol)
• the compounds of the formula ⁇ antagonists of the M3 receptor (muscarinic receptor subtype 3) are found.
• the compounds according to the invention have Ki values of less than 10nM with regard to the affinity for the M3 receptor. These values were determined according to the procedure described below.
• 3H-NMS was obtained from Amersham, Braunschweig, with a specific radioactivity of 3071 GBq / mmol (83 Ci / mmol). All other raegantien were obtained from Serva, Heidelberg and Merck, Darmstadt.
• the binding assay was carried out in a final volume of 1 ml and was composed of 100 ⁇ l of labeled substance in various concentrations, 100 ⁇ l of radioligand (3H-N-methylscopolamine 2 nmol / L (3H-NMS), 200 l of membrane preparation and 600 ⁇ l of HEPES Buffer (20 mmol / L HEPES, 10 mmol / L MgCI2, 100 mmol / L NaCI, adjusted to pH 7.4 with 1 mol / L NaOH. We determined the nonspecific binding by 10 / mol / L atropine. The incubation of 45 min was carried out as a duplicate determination at 37 ° C.
• Radioactivity of the filter mats were measured simultaneously using a two-dimensional, digital autoradiograph (Berthold, Wildbad, type 3052).
• the compounds of formula 1 according to the invention are characterized by a wide range of possible uses in the therapeutic field.
• the compounds of the formula ⁇ according to the invention can preferably be used due to their pharmaceutical activity as an anticholinergic.
• the compounds of the general formula ⁇ can also be used for the treatment of vagal sinus bradycardia and for the treatment of cardiac arrhythmias.
• the compounds according to the invention can also be used for the treatment of spasms, for example in the gastrointestinal tract, with therapeutic benefits. They can also be used in the treatment of spasms in urinary passages and, for example, in menstrual cramps.
• the therapy of asthma and COPD by means of the compounds of the formula I according to the invention is of particular importance.
• the compounds of general formula 1 can be used alone or in combination with other active compounds of formula 1 according to the invention. If appropriate, the compounds of the general formula 1 can also be used in combination with other pharmacologically active compounds. These are, in particular, betamimetics, antiallergics, PAF antagonists, PDE IV inhibitors, leukotriene antagonists, p38 kinase inhibitors, EGFR kinase inhibitors and corticosteroids, and combinations of active substances thereof.
• betamimetics which can be used according to the invention as a combination with the compounds of formula 1, there may be mentioned compounds which are selected from the group consisting of bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol , Procaterol, reproterol, salmeterol, sulfonterol, terbutaline, tolubuterol, 4-hydroxy-7- [2 - ⁇ [2 - ⁇ [3- (2- ⁇ henylethoxy) propyl] sulfonyl ⁇ ethyl] -amino ⁇ ethyl] -2 (3H ) - benzothiazolone, 1 - (2-fluoro-4-hydroxyphenyl) -2- [4- (1 -benzimidazolyl) -2-methyl-2-butylaminojethanol, 1 - [3- (4
• Such betamimetics are particularly preferably used in combination with the compounds of the formula I according to the invention which are selected from the group consisting of fenoterol, formoterol, salmeterol, 1- [3- (4-methoxybenzylamino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylaminojethanol, 1 - [2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl] -2- [3 - (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [ 3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1 - [2H- 5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl]
• the compounds formoterol come from the above-mentioned beta mimetics and salmeterol, optionally in the form of their racemates, their enantiomers, their diastereomers, and optionally their pharmacologically acceptable acid addition salts and hydrates.
• the acid addition salts of the betamimetics are preferred, for example, selected from the group consisting of hydrochloride,
• the salts are particularly preferably selected from hydrochloride, sulfate and xinafoate, of which the xinafoate is particularly preferred.
• the salts are particularly preferably selected from hydrochloride, sulfate and fumarate, of which the hydrochloride and fumarate are particularly preferred. According to the invention, formoterol fumarate is of outstanding importance.
• corticosteroids which can optionally be used in combination with the compounds of the formula 1_, are understood to mean compounds which are selected from the group consisting of flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide , GW 215864, KSR 592, ST-126 and Dexametasone.
• the corticosteroids are preferably selected from the group consisting of flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide and dexametasone, here the budesonide, fluticasone, mometasone and ciclesonide, in particular the budesonasone and one in particular Importance.
• steroids is used in the context of the present patent application instead of the term corticosteroids.
• Reference to steroids in the context of the present invention includes reference to salts or derivatives that can be formed by the steroids.
• salts or derivatives are: sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. If appropriate, the corticosteroids can also be present in the form of their hydrates.
• PDE-IV inhibitors which can be used according to the invention as a combination with the compound of formula 1
• compounds which are selected from the group consisting of Enprofylline, Roflumilast, Ariflo, Bay-198004, CP-325,366 , BY343, D-4396 (Sch-351591), V-11294A and AWD-12-281.
• Preferred PDE-IV inhibitors are selected from the group consisting of Enprofylline, Roflumilast, Ariflo and AWD-12-281, with AWD-12-281 being particularly preferred as a combination partner with the compound of the formula I_ according to the invention.
• PDE-IV inhibitors include a reference to their pharmacologically acceptable acid addition salts which may exist.
• the physiologically tolerable acid addition salts which can be formed by the abovementioned PDE IV inhibitors are understood as pharmaceutically tolerable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid , Citric acid, tartaric acid or maleic acid.
• the salts selected from the group consisting of acetate, hydrochloride, hydrobromide, sulfate, phosphate and methanesulfonate are preferred according to the invention.
• dopamine agonists which can optionally be used in combination with the compounds of the formula 1, are understood to mean compounds which are selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole , Roxindol, Ropinirol, Talipexol, Tergurid and Viozan.
• dopamine agonists preference is given to using dopamine agonists as combination partners with the compounds of the formula 1 which are selected from the group consisting of pramipexole, talipexole and viozan, pramipexole being of particular importance.
• a reference to the above-mentioned dopamine agonists includes a reference to their optionally existing pharmacologically acceptable acid addition salts and, if appropriate, their hydrates.
• physiologically acceptable acid addition salts that are mentioned above
• Dopamine agonists can be formed, for example pharmaceutically acceptable salts are understood, which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.
• antiallergics which can be used according to the invention as a combination with the compounds of the formula I include epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine, Doxylamine, chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozin.
• Preferred antiallergics which can be used in the context of the present invention in combination with the compounds of the formula 1 according to the invention are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, ebastine, desloratidine and mizolastine, with epinastine and desloratidine being particularly preferred.
• a reference to the above-mentioned antiallergics includes a reference to their pharmacologically acceptable acid addition salts which may exist.
• 4 - [(3 ⁇ chloro-4-fluorophenyl) amino] -7- [4 may be mentioned as a particularly preferred example of EGFR kinase inhibitors which can be used in combination with the compounds of the formula 1 according to the invention - ((R) -6-methyl-2-oxo-morpholin-4-yl) butyloxy] -6 - [(vinylcarbonyl) amino] -quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino ] -7- [4 - ((S) -6-methyl-2-oxo-morpholin-4-yl) butyloxy] -6- [(vinylcarbonyl) amino] -quinazoline, 4 - [(3-chloro-4 -fluorophenyl) amino] -7- (2- ⁇ 4 - [(S) - (2-oxo-tetrahydrofuran-5-yl) carbonyl] piperazin-1-
• a reference to the aforementioned EGFR kinase inhibitors includes a reference to their pharmacologically acceptable acid addition salts which may exist.
• physiological or pharmacologically acceptable acid addition salts which can be formed by the EGFR kinase inhibitors are understood according to the invention to be pharmaceutically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or are maleic acid.
• the salts of the EGFR kinase inhibitors are preferably selected from the salts of acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.
• 1 - [5-te / t-butyl-2-p-tolyl-2H-pyrazole-3 may be mentioned as particularly preferred -yl] -3- [4- (2-morpholin-4-ylethoxy) naphthalen-1-yl] urea; 1 - [5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (1 - oxothiomorpholin-4-yl) ethoxy) naphthalen-1-yl] - urea; 1 - [5-fert-butyl-2-
• a reference to the above-mentioned p38 kinase inhibitors in the context of the present invention includes a reference to their pharmacologically acceptable acid addition salts which may exist.
• the physiologically or pharmacologically acceptable acid addition salts which can be formed by the p38 kinase inhibitors are understood to be pharmaceutically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, Are lactic acid, citric acid, tartaric acid or maleic acid.
• the combination of steroids, PDE IV inhibitors or betamimetics is particularly preferred from the compound classes mentioned above.
• the combination with beta mimetics, in particular with long-acting beta mimetics, is of particular importance.
• the combination of the compounds of the formula ⁇ with salmeterol or formoterol is to be regarded as particularly preferred.
• Suitable forms of application for the application of the compounds of the formula ⁇ are, for example, tablets, capsules, suppositories, solutions etc.
• the inhalative application of the compounds according to the invention is particularly important (in particular in the treatment of asthma or COPD).
• the proportion of the pharmaceutically active compound (s) should in each case be in the range from 0.05 to 90% by weight, preferably 0.1 to 50% by weight, of the total composition.
• Corresponding tablets can be mixed, for example, by mixing the active ingredient (s) with known auxiliaries, for example inert diluents, such as calcium carbonate, calcium phosphate or milk sugar, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or agents to achieve the depot effect, such as carboxymethyl cellulose, Cellulose acetate phthalate, or polyvinyl acetate can be obtained.
• auxiliaries for example inert diluents, such as calcium carbonate, calcium phosphate or milk sugar, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or agents to achieve the depot effect, such as carboxymethyl cellulose, Cellulose acetate phthalate, or polyvinyl acetate can be obtained.
• coated tablets can be produced by coating cores produced analogously to the tablets with agents commonly used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
• the core can also consist of several layers in order to achieve a depot effect or to avoid incompatibilities.
• the coated tablet shell can also consist of several layers in order to achieve a depot effect, it being possible to use the auxiliaries mentioned above for the tablets.
• Juices of the active substances or combinations of active substances according to the invention can additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar as well as a taste-improving agent, e.g. Flavorings, such as vanillin or orange extract, contain. They can also contain suspending agents or thickening agents, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
• a sweetener such as saccharin, cyclamate, glycerol or sugar
• a taste-improving agent e.g.
• Flavorings such as vanillin or orange extract
• suspending agents or thickening agents such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
• Solutions are made in the usual way, e.g. with the addition of isotonants, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and / or dispersants, where, for example, when using water as a diluent, organic solvents can optionally be used as solubilizers or auxiliary solvents , manufactured and filled into injection bottles or ampoules or infusion bottles.
• isotonants e.g. with the addition of isotonants, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and / or dispersants, where, for example, when using water as a diluent, organic solvents can optionally be used as solubilizers or auxiliary solvents , manufactured and
• the capsules containing one or more active ingredients or combinations of active ingredients can be produced, for example, by mixing the active ingredients with inert carriers, such as milk sugar or sorbitol, and encapsulating them in gelatin capsules.
• inert carriers such as milk sugar or sorbitol
• Suitable suppositories can be produced, for example, by mixing them with carrier agents such as neutral fats or polyethylene glycol or its derivatives.
• carrier agents such as neutral fats or polyethylene glycol or its derivatives.
• auxiliaries are water, pharmaceutically acceptable organic solvents, such as paraffins (for example petroleum fractions), oils of vegetable origin (for example peanut or sesame oil), mono- or polyfunctional alcohols (for example ethanol or glycerol), carriers such as natural rock meal (for example kaolins, Clays, talc, chalk) synthetic rock flour (e.g. highly disperse Silica and silicates), sugar (e.g. cane, milk and glucose) emulsifiers (e.g.
• lignin e.g. lignin, sufite liquor, methyl cellulose, starch and polyvinylpyrrolidone
• lubricants e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate
• the tablets can of course also contain additives, such as e.g. Contain sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like.
• Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting.
• the active ingredients can be mixed with various flavor enhancers or colorants.
• Inhalable dosage forms include inhalable powders, metered-dose aerosols containing propellants or propellant-free inhalation solutions.
• propellant-free inhalation solutions also includes concentrates or sterile, ready-to-use inhalation solutions.
• Inhalable powders which can be used according to the invention may contain 1 either alone or in a mixture with suitable physiologically acceptable auxiliaries. If the active ingredients 1 are contained in a mixture with physiologically acceptable auxiliaries, the following physiologically acceptable auxiliaries can be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose,
• Mono- or disaccharides are preferably used, the use of lactose or glucose being preferred, particularly but not exclusively in the form of their hydrates. Lactose, most preferably lactose monohydrate, is used as an auxiliary as particularly preferred in the sense of the invention.
• the auxiliaries have a maximum average particle size of up to 250 / ym, preferably between 10 and 150 ⁇ m, particularly preferably between 15 and 80 ⁇ m. If appropriate, it may appear sensible to add finer excipient fractions with an average particle size of 1 to 9 ⁇ m to the excipients mentioned above. The latter finer excipients are also selected from the group of excipients that can be used.
• micronized active ingredient 1 preferably with an average particle size of 0.5 to 10 ⁇ m, particularly preferably 1 to 5 ⁇ m, is admixed with the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronizing and by finally mixing the constituents are known from the prior art. The inhalable powders according to the invention can be applied using inhalers known from the prior art.
• Inhalation aerosols containing propellant gas according to the invention can contain dissolved in the propellant gas or in dispersed form. Here you can 1. in separate
• propellant gases which can be used to produce the inhalation aerosols are known from the prior art.
• Suitable propellants are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halogenated hydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
• the above-mentioned propellant gases can be used alone or in mixtures thereof.
• Particularly preferred propellants are halogenated alkane derivatives selected from TG 134a and TG227 and mixtures thereof.
• the inhalation aerosols containing propellant gas can also contain further constituents such as cosolvents, stabilizers, surfactants, antioxidants, lubricants and agents for adjusting the pH. All of these components are known in the art.
• the active ingredients 1 according to the invention can be applied in the form of propellant-free inhalation solutions and inhalation suspensions.
• Aqueous or alcoholic, preferably ethanolic, solutions are suitable as solvents for this Consideration.
• the solvent can only be water or it is a mixture of water and ethanol.
• the relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70 volume percent, in particular up to 60 volume percent and particularly preferably up to 30 volume percent.
• the remaining volume percentages are filled up with water.
• the solutions or suspensions containing I are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. Acids selected from inorganic or organic acids can be used to adjust this pH.
• Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid.
• Examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others.
• Preferred inorganic acids are hydrochloric acid, sulfuric acid. It is also possible to use the acids which already form an acid addition salt with one of the active ingredients. Ascorbic acid, fumaric acid and citric acid are preferred among the organic acids.
• mixtures of the acids mentioned can also be used, in particular in the case of acids which, in addition to their acidifying properties, also have other properties, for example as flavorings, antioxidants or complexing agents, such as, for example, citric acid or ascorbic acid.
• hydrochloric acid is particularly preferably used to adjust the pH.
• the addition of editic acid (EDTA) or one of the known salts thereof, sodium edetate, as a stabilizer or complexing agent may optionally be dispensed with.
• Other embodiments include this connection (s).
• the content based on sodium edetate is below 100 mg / 100 ml, preferably below 50 mg / 100 ml, particularly preferably below 20 mg / 100 ml.
• Inhalation solutions in which the sodium edetate content is 0 to 10 mg / 100 ml are generally preferred.
• Co-solvents and / or other auxiliaries can be added to the propellant-free inhalation solutions.
• Preferred co-solvents are those which contain hydroxyl groups or other polar groups, for example alcohols - in particular isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
• auxiliaries and additives are understood to mean any pharmacologically acceptable substance which is not an active substance but can be formulated together with the active substance (s) in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation.
• These substances preferably do not develop or in the context of the desired therapy, no significant or at least no undesirable pharmacological effects.
• the auxiliaries and additives include, for example, surface-active substances, such as, for example, soy lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives which guarantee or extend the useful life of the finished pharmaceutical formulation, flavors, vitamins and / or other additives known in the prior art.
• the additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.
• the preferred auxiliaries include antioxidants, such as, for example, ascorbic acid, unless already used for adjusting the pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human organism.
• Preservatives can be used to protect the formulation from contamination with germs. Suitable preservatives are those known from the prior art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.
• the preservatives mentioned above are preferably present in concentrations of up to 50 mg / 100 ml, particularly preferably between 5 and 20 mg / 100 ml.
• Preferred formulations contain water and the solvent
• Active ingredient I only benzalkonium chloride and sodium edetate.
• sodium edetate is dispensed with.
• the dosage of the compounds according to the invention is of course highly dependent on the type of application and the disease to be treated.
• the compounds of formula 1 When administered by inhalation, the compounds of formula 1 are highly effective even at doses in the ⁇ g range. Even above the ⁇ g range, the compounds of formula 1 can be used expediently.
• the dosage may then ⁇ for example, be in the gram range.
• the compounds according to the invention can be administered with a higher dosage (for example, but not in a limiting manner in the range from 1 to 1000 mg).
• the finely ground active ingredient, milk sugar and part of the corn starch are mixed together.
• the mixture is sieved, whereupon it is moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried.
• the granules, the rest of the corn starch and the magnesium stearate are sieved and mixed together.
• the mixture is compressed into tablets of a suitable shape and size.
• the active ingredient is dissolved in water at its own pH or, if appropriate, at pH 5.5 to 6.5, and sodium chloride is added as an isotonic agent.
• the solution obtained is filtered pyrogen-free and the filtrate is filled into ampoules under aseptic conditions, which are then sterilized and sealed.
• the ampoules contain 5 mg, 25 mg and 50 mg of active ingredient.
• Active ingredient 1 0.005
• Sorbitan trioleate 0.1 monofluorotrichloromethane
• the suspension is filled into a conventional aerosol container with a metering valve. 50 ⁇ l of suspension are preferably dispensed per actuation. If desired, the active ingredient can also be dosed higher (e.g. 0.02% by weight).
• the inhalable powder is prepared in the usual way by mixing the individual components.
• Active ingredient 1 10 ⁇ g
• the inhalable powder is prepared in the usual way by mixing the individual components.

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• 2002
  • 2002-03-16 DE DE10211700A patent/DE10211700A1/de not_active Withdrawn
• 2003
  • 2003-03-10 CA CA002476746A patent/CA2476746A1/en not_active Abandoned
  • 2003-03-10 AT AT03706609T patent/ATE341547T1/de active
  • 2003-03-10 DE DE50305263T patent/DE50305263D1/de not_active Expired - Lifetime
  • 2003-03-10 EP EP03706609A patent/EP1487831B1/de not_active Expired - Lifetime
  • 2003-03-10 JP JP2003576433A patent/JP2005520832A/ja active Pending
  • 2003-03-10 WO PCT/EP2003/002418 patent/WO2003078428A1/de active IP Right Grant
  • 2003-03-10 ES ES03706609T patent/ES2272947T3/es not_active Expired - Lifetime
  • 2003-03-10 AU AU2003208703A patent/AU2003208703A1/en not_active Abandoned

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